IL-6 is a multifunctional cytokine that functions as an autocrine growth factor for AIDS-derived Kaposi's sarcoma (KS) cells. We report that IL-6 is highly inducible at both the mRNA and protein levels in cultured KS cells by multiple agents, yet the effect of the IL-6 on the proliferation of KS cells is dependent on the agent responsible for its induction. Both IL-1 beta and the synthetic dsRNA, poly (I:C), induced high levels of IL-6 mRNA and protein expression, whereas LPS and TNF-alpha led to only modest increases in IL-6 protein and mRNA. When KS cells were incubated with poly (I:C) in combination with either IL-1 beta or TNF-alpha, there was a synergistic increase in the level of IL-6 production, whereas LPS and TNF-alpha in combination led to only an additive increase in the level of IL-6 production. Exogenous IL-6 was shown to induce proliferation in KS cells, yet there was a dramatic inhibition of proliferation in response to poly (I:C), despite the high levels of IL-6 produced. This inhibition of proliferation by poly (I:C) was unlikely as a result of expression of class I IFN in response to the poly (I:C) because high concentrations of exogenous IFN-alpha had no demonstrable effect on [3H]TdR incorporation under conditions in which poly (I:C) caused a 90% decrease in [3H]TdR incorporation. Pretreatment of KS cells with poly (I:C) for 24 h followed by removal of the poly (I:C) led to high levels of IL-6 secreted into medium that induced proliferation in KS cells. These data suggest that in vivo, multiple agents that occur in response to infection and systemic disease could induce IL-6 production by KS cells, yet the ability of the IL-6 to influence proliferation of KS cells is dependent on the context in which the IL-6 is induced.